Back to EveryPatent.com
| United States Patent |
5,627,203
|
|
Rault
, et al.
|
May 6, 1997
|
Tricyclic oxime ethers
Abstract
The present invention relates to compounds of formula (I):
##STR1##
wherein A, x, y, R.sub.1, R.sub.2 and R.sub.3 are as defined in the
description. The compounds are useful for treating diseases requiring a
selective serotonin reuptake site and 5-HT.sub.2c or 5-HT.sub.3 ligand.
| Inventors:
|
Rault; Sylvain (Moult, FR);
Robba; Max (Paris, FR);
Lancelot; Jean-Charles (Le Bourg, FR);
Prunier; Herv e (Caen, FR);
Renard; Pierre (Versailles, FR);
Pfeiffer; Bruno (Eaubonne, FR);
Guardiola-Lemaitre; B eatrice (Saint-Cloud, FR);
Rettori; Marie-Claire (Courbevoie, FR)
|
| Assignee:
|
Adir et Compagnie (Courbevoie, FR)
|
| Appl. No.:
|
576678 |
| Filed:
|
December 21, 1995 |
Foreign Application Priority Data
| Current U.S. Class: |
514/411; 514/321; 546/192; 548/428 |
| Intern'l Class: |
A61K 031/40; C07D 513/14 |
| Field of Search: |
514/321,411
546/192
548/428
|
References Cited
U.S. Patent Documents
| 3903164 | Sep., 1975 | Goransson-Dahlander | 564/257.
|
| 4308399 | Dec., 1981 | Takacs et al. | 564/257.
|
| 4395413 | Jul., 1983 | Budai et al. | 564/257.
|
Other References
Kilpatrick, Gavin J., et al., 5-HT.sub.3 Receptors, Medicinal Research
Reviews, vol. 10, No. 4, 441-475 (1990).
Hoyer, Danies, et al., VII. International Union of Pharmacology
Classification of Receptors for 5-Hydroxytryptamine (Serotonin),
Pharmacology Reviews, vol. 46, No. 2, 157-203 (1994).
Langer, S.Z., et al., Inhibitors of Serotonin Uptake, in Serotonin from
Cell Biology to Pharmacology and Therapeutics, (P.M. Vanhoutte, et al.
eds.) 197-205 (1993 Kluwer Academic Publishers).
|
Primary Examiner: Haley; Jacqueline
Attorney, Agent or Firm: The Firm of Gordon W. Hueschen
Claims
We claim:
1. A compound selected from those of formula (I):
##STR140##
wherein R.sub.1 is selected from:
hydrogen,
alkyl,
alkenyl,
cycloalkyl,
cycloalkyl in which the alkyl chain is straight or branched and has 1 to 4
carbon atoms inclusive,
hydroxy,
alkoxy,
unsubstituted or substituted phenyl,
unsubstituted of substituted phenylalkyl in which the alkyl chain is
straight or branched and has 1 to 4 carbon atoms inclusive,
unsubstituted or substituted phenoxy, and
unsubstituted or substituted phenylalkoxy in which the alkyl chain is
straight or branched and has 1 to 4 carbon atoms inclusive,
or R.sub.1 forms with R.sub.2 and the chain
##STR141##
carrying them a nitrogen-containing ring system having 5 to 8 ring
members inclusive,
R.sub.2 and R.sub.3 are each selected, independently of the other, from:
hydrogen,
alkyl,
alkenyl,
cycloalkyl,
unsubstituted or substituted indanyl,
cycloalkylalkyl in which the alkyl chain is straight or branched and has 1
to 4 carbon atoms inclusive,
unsubstituted or substituted phenyl, and
unsubstituted or substituted phenylalkyl in which the alkyl chain is
straight or branched and has 1 to 4 carbon atoms inclusive,
or R.sub.2 and R.sub.3 form together with the nitrogen atom carrying them
a heterocyclic system selected from:
##STR142##
wherein: m is 0, 1, 2, 3, or 4,
n is 0, 1, or 2,
Y' is selected from oxygen, sulfur and
##STR143##
R.sub.4 being selected from: hydrogen,
alkyl, and
unsubstituted or substituted --(CH.sub.2).sub..sigma. -phenyl, wherein
.sigma. is 0, 1, 2, 3, or 4,
x and y are identical or different and are 0, 1, 2, 3, or 4,
A represents:
a group of formula (.alpha.):
##STR144##
and thus forms with the heterocyclic system carrying it a
thieno[2,3-d]pyrrolo[1,2-a]pyrrole of the formula (I.sub..alpha.):
##STR145##
wherein R.sub.1, R.sub.2, R.sub.3, x, and y are as defined hereinbefore
and R.sub.5 and R.sub.6, which are identical or different, each
represents, independently of the other, a group selected from:
hydrogen,
alkyl,
hydroxy,
alkoxy,
halogen,
trifluoromethyl,
alkoxycarbonyl,
unsubstituted or substituted --(CH.sub.2).sub.p -phenyl wherein p is 0, 1,
2, 3, or 4, and
unsubstituted or substituted --O--(CH.sub.2).sub.p' -phenyl wherein p' is
0, 1, 2, 3, or 4,
a group of formula (.beta.):
##STR146##
and thus forms with the heterocyclic system carrying it a
thieno[3,2-d]pyrrolo[1,2-a]pyrrole of the formula (I.sub..beta.):
##STR147##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, x and y are as
defined hereinbefore,
a group of formula (.gamma.):
##STR148##
and thus forms with the heterocyclic system carrying it a
pyrrolo[1,2-a]indole of the formula (I.gamma.):
##STR149##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, x and y are as
defined hereinbefore,
their cis or trans isomers in respect of the oxime ether,
their enantiomers or diastereoisomers, and
their hydrates and/or pharmaceutically-acceptable addition salts with an
acid or a base,
it being understood, unless specified otherwise, that:
the terms "alkyl" and "alkoxy" represent a straight-chain or branched group
having 1 to 6 carbon atoms inclusive,
the term "alkenyl" represents a straight-chain or branched unsaturated
group having 2 to 6 carbon atoms inclusive,
the term "cycloalkyl" represents a carbon ring system having 3 to 8 ring
members inclusive,
the expressions "substituted indanyl", "substituted phenyl", "substituted
phenoxy", "substituted phenylalkyl", "substituted --(CH.sub.2).sub..sigma.
-phenyl", "substituted --(CH.sub.2).sub.p -phenyl", substituted
"--O--(CH.sub.2).sub.p' -phenyl" and "substituted phenylalkoxy" denote
that the phenyl radical is substituted by one or more identical or
different substituents selected from alkyl, alkoxy, hydroxy, halogen,
trifluoromethyl, nitrile and nitro.
2. A compound according to claim 1 wherein A represents a group of formula
(.alpha.):
##STR150##
and thus forms with the heterocyclic system carrying it a
thieno[2,3-d]pyrrolo[1,2-a]pyrrole of the formula (I.sub..alpha.):
##STR151##
wherein R.sub.1, R.sub.2, R.sub.3, x, and y are as defined in claim 1 and
R.sub.5 and R.sub.6, which are identical or different, each represents,
independently of the other, a group selected from:
hydrogen,
alkyl,
hydroxy,
alkoxy,
halogen,
trifluoromethyl,
alkoxycarbonyl,
unsubstituted or substituted --(CH.sub.2).sub.p -phenyl wherein p is 0, 1,
2, 3, or 4, and
unsubstituted or substituted --O--(CH.sub.2).sub.p' -phenyl wherein p' is
0, 1, 2, 3, or 4,
their cis or trans isomers in respect of the oxime ether,
their enantiomers or diastereoisomers, and
their hydrates and/or pharmaceutically-acceptable addition salts with an
acid or a base,
it being understood, unless specified otherwise, that:
the terms "alkyl" and "alkoxy" represent straight-chain or branched groups
having 1 to 6 carbon atoms inclusive,
the expressions "substituted --(CH.sub.2).sub.p -phenyl" and "substituted
--O--(CH.sub.2).sub.p' -phenyl" denote that the phenyl radical is
substituted by one or more identical or different substituents selected
from alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitrile and nitro.
3. A compound according to claim 1 wherein A represents a group of formula
(.beta.):
##STR152##
and thus forms with the heterocyclic system carrying it a
thieno[3,2-d]pyrrolo[1,2-a]pyrrole of the formula (I.sub..beta.):
##STR153##
wherein R.sub.1, R.sub.2, R.sub.3, x and y are as defined in claim 1 and
R.sub.5 and R.sub.6, which are identical or different, each represents,
independently of the other, a group selected from:
hydrogen,
alkyl,
hydroxy,
alkoxy,
halogen,
trifluoromethyl,
alkoxycarbonyl,
unsubstituted or substituted --(CH.sub.2).sub.p -phenyl wherein p is 0, 1,
2, 3, or 4, and
unsubstituted or substituted --O--(CH.sub.2).sub.p' -phenyl wherein p' is
0, 1, 2, 3, or 4,
their cis or trans isomers in respect of the oxime ether,
their enantiomers or diastereoisomers, and
their hydrates and/or pharmaceutically-acceptable addition salts with an
acid or a base,
it being understood, unless specified otherwise, that:
the terms "alkyl" and "alkoxy" represent straight-chain or branched groups
having 1 to 6 carbon atoms inclusive,
the expressions "substituted --(CH.sub.2).sub.p -phenyl" and "substituted
--O--(CH.sub.2).sub.p' -phenyl" denote that the phenyl radical is
substituted by one or more identical or different substituents selected
from alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitrile and nitro.
4. A compound according to claim 1 wherein A represents a group of formula
(.gamma.):
##STR154##
and forms with the heterocyclic system carrying it a pyrrolo[1,2-a]indole
of the formula (I.gamma.):
##STR155##
wherein R.sub.1, R.sub.2, R.sub.3, x, and y are as defined in claim 1 and
R.sub.5 and R.sub.6, which are identical or different, each represents,
independently of the other, a group selected from:
hydrogen,
alkyl,
hydroxy,
alkoxy,
halogen,
trifluoromethyl,
alkoxycarbonyl,
unsubstituted or substituted --(CH.sub.2).sub.p -phenyl wherein p is 0, 1,
2, 3, or 4, and
unsubstituted or substituted --O--(CH.sub.2).sub.p' -phenyl wherein p' is
0, 1, 2, 3, or 4,
their cis or trans isomers in respect of the oxime ether,
their enantiomers or diastereoisomers, and
their hydrates and/or pharmaceutically-acceptable addition salts with an
acid or a base,
it being understood, unless specified otherwise, that:
the terms "alkyl" and "alkoxy" represent straight-chain or branched groups
having 1 to 6 carbon atoms inclusive,
the expressions "substituted --(CH.sub.2).sub.p -phenyl" and "substituted
--O--(CH.sub.2).sub.p' -phenyl" denote that the phenyl radical is
substituted by one or more identical or different substituents selected
from alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitrile and nitro.
5. A compound according to claim 1, which is selected from
3-methyl-8-{[3-(N,N-dimethylamino)-1-phenyl-n-prop-1-yloxy]imino}thieno[2,
3-d]pyrrolo[1,2-a]pyrrole for which the formula is shown below, and its Z
and E isomers and its enantiomers, isolated or in the form of a mixture,
and its pharmaceutically-acceptable addition salts with an acid
##STR156##
6. A compound according to claim 1 which is selected from
3-methyl-8-{[2-(N-benzylamino)ethoxy]imino}thieno[2,3-d]pyrrolo[1,2-a]pyrr
ole for which the formula is shown below, and its Z and E isomers, isolated
or in the form of a mixture, and its pharmaceutically-acceptable addition
salts with an acid
##STR157##
7. A compound according to claim 1, which is selected from
3-methyl-8-{[2-(N,N-dimethylamino)-n-prop-1-yloxy]imino}thieno[2,3-d]pyrro
lo[1,2-a]pyrrole for which the formula is shown below, and its Z and E
isomers and its enantiomers, isolated or in the form of a mixture, and its
pharmaceutically-acceptable addition salts with an acid
##STR158##
8. A compound according to claim 1, which is selected from
8-{[2-(N,N-dimethylamino)ethoxy]imino}thieno[3,2-d]pyrrolo[1,2-a]pyrrole
for which the formula is shown below, and its Z and E isomers, isolated or
in the form of a mixture, and its pharmaceutically-acceptable addition
salts with an acid
##STR159##
9. A compound according to claim 1, which is selected from
9-{[2-(N,N-dimethylamino)-n-prop-1-yloxy]imino}pyrrolo[1,2-a]indole for
which the formula is shown below, and its Z and E isomers and its
enantiomers, isolated or in the form of a mixture, and its
pharmaceutically-acceptable addition salts with an acid
##STR160##
10. A method for treating a mammal afflicted with a disease requiring a
selective seratonin reuptake site and 5-HT.sub.2c and/or 5-HT.sub.3 ligand
comprising the step of administering to said mammal an amount of a
compound of claim 1 which is effective for alleviation of said disease.
11. A pharmaceutical composition useful as a 5-HT.sub.2c and/or 5-HT.sub.3
ligand provider comprising an effective amount of a compound as claimed in
claim 1, together with a pharmaceutically-acceptable excipient.
Description
The present invention relates to new tricyclic oxime ethers, to processes
for their preparation and to pharmaceutical compositions containing them.
Some examples of mono- or poly-cyclic oxime ethers are known from the
literature. Of those sources, especially the patents BAYER EP 544 168 and
EP 544 169 may be mentioned, which claim oxime ethers corresponding to the
following general formulae:
##STR2##
Those compounds are described as being reverse transcriptase inhibitors
that can be used in the treatment of retrovirus disorders such as AIDS.
The Applicant has discovered new oxime ethers having a completely original
tricyclic structure which are unexpectedly characterised by a very strong
affinity for 5HT.sub.2C and/or 5HT.sub.3 receptors and also for serotonin
reuptake sites. That high affinity is associated with a prominent
selectivity with vis a vis other serotoninergic receptors.
The potential and the therapeutic value of compounds that bind strongly to
5HT.sub.2C and/or 5HT.sub.3 receptors are well known and in that
connection the following reviews may usefully be referred to:
G. J. KILPATRICK "5HT.sub.3 receptors" (Medicinal Research Reviews, 1990,
10(4), p 441-475).
D. HOYER et al "VII International Union of Pharmacology Classification of
Receptor for 5-hydroxytryptamine (Serotonin)" (Pharmacological Reviews,
1994, 46 (2) pp 157-203).
The same applies in respect of compounds that inhibit the reuptake of
serotonin; see in that connection the review by S. Z. LANGER and D. GRAHAM
entitled "Inhibitors of serotonin uptake" taken from the work "SEROTONIN
from cell biology to pharmacology and therapeutics" (P. M. VANHOUTTE et
al. (eds.) 1993 Klurver Academic Publisher, the Netherlands).
The value of the compounds of the present invention is all the greater
since they act powerfully and simultaneously at those different sites of
action, rendering them very valuable therapeutically.
The invention relates more especially to compounds of formula (I):
##STR3##
wherein R.sub.1 is selected from:
hydrogen,
alkyl,
alkenyl,
cycloalkyl,
cycloalkylalkyl of which the straight or branched alkyl chain has from 1 to
4 carbon atoms,
hydroxy,
alkoxy,
optionally substituted phenyl,
optionally substituted phenylalkyl of which the straight or branched alkyl
chain has from 1 to 4 carbon atoms,
optionally substituted phenoxy, and
optionally substituted phenylalkoxy of which the straight or branched alkyl
chain has from 1 to 4 carbon atoms,
or R.sub.1 forms with R.sub.2 and the chain
##STR4##
carrying them a nitrogen-containing ring system having from 5 to 8 ring
members,
R.sub.2 and R.sub.3 are each selected, independently of the other, from:
hydrogen,
alkyl,
alkenyl,
cycloalkyl,
optionally substituted indanyl,
cycloalkylalkyl of which the straight or branched alkyl chain has from 1 to
4 carbon atoms,
optionally substituted phenyl, and
optionally substituted phenylalkyl of which the straight or branched alkyl
chain has from 1 to 4 carbon atoms,
or R.sub.2 and R.sub.3 form together with the nitrogen atom carrying them
a heterocyclic system selected from:
##STR5##
wherein: m is an integer of which the value may be 0, 1, 2, 3, or 4,
n is an integer of which the value may be 0, 1, or 2,
Y' is selected from oxygen, sulfur and the group
##STR6##
R.sub.4 being selected from:
hydrogen,
alkyl, and
optionally substituted --(CH.sub.2).sub..sigma. -phenyl, wherein .sigma. is
an integer of which the value may be 0, 1, 2, 3, or 4,
x and y represent identical or different integers of which the values may
each, independently of the other, be 0, 1, 2, 3, or 4,
A represents:
a group of formula (.alpha.):
##STR7##
and thus forms with the heterocyclic system carrying it a
thieno[2,3-d]pyrrolo[1,2-a]pyrrole of the general formula (I.sub..alpha.):
##STR8##
wherein R.sub.1, R.sub.2, R.sub.3, x, and y are as defined hereinbefore
and R.sub.5 and R.sub.6, which are identical or different, each
represents, independently of the other, a group selected from:
hydrogen,
alkyl,
hydroxy,
alkoxy,
halogen,
trifluoromethyl,
alkoxycarbonyl,
optionally substituted --(CH.sub.2).sub.p -phenyl wherein p is an integer
of which the value may be 0, 1, 2, 3, or 4, and
optionally substituted --O--(CH.sub.2).sub.p' -phenyl wherein p' is an
integer of which the value may be 0, 1, 2, 3, or 4,
a group of formula (.beta.):
##STR9##
and thus forms with the heterocyclic system carrying it a
thieno[3,2-d]pyrrolo[1,2-a]pyrrole of the general formula (I.sub..beta.):
##STR10##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, x and y are as
defined hereinbefore,
a group of formula (.gamma.):
##STR11##
and thus forms with the heterocyclic system carrying it a
pyrrolo[1,2-a]indole of the general formula (I.gamma.):
##STR12##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, x and y are as
defined hereinbefore,
their cis or trans isomers in respect of the oxime ether,
their enantiomers or diastereoisomers, and
their hydrates and/or pharmaceutically-acceptable addition salts with an
acid or a base,
it being understood, unless specified otherwise, that:
the terms "alkyl" and "alkoxy" represent straight-chain or branched groups
having from 1 to 6 carbon atoms,
the term "alkenyl" represents a straight-chain or branched unsaturated
carbon-containing group having from 2 to 6 carbon atoms,
the term "cycloalkyl" represents a carbon ring system having from 3 to 8
ring members,
the expressions "optionally substituted indanyl", "optionally substituted
phenyl", "optionally substituted phenoxy", "optionally substituted
phenylalkyl", "optionally substituted --(CH.sub.2).sub..sigma. -phenyl",
"optionally substituted --(CH.sub.2).sub.p -phenyl", optionally
substituted "--O--(CH.sub.2).sub.p' -phenyl" and "optionally substituted
phenylalkoxy" denote that the phenyl radical may optionally be substituted
by one or more identical or different substituents selected from alkyl,
alkoxy, hydroxy, halogen, trifluoromethyl, nitrile and nitro.
Among the acids that may be used to form a pharmaceutically-acceptable
addition salt with the compounds of the invention there may be mentioned
by way of example, and in a non-limiting manner, hydrochloric, sulfuric,
phosphoric, tartaric, malic, maleic, succinic, fumaric, oxalic,
methanesulfonic, ethanesulfonic, camphoric and citric acid.
Among the bases that may be used to form a pharmaceutically-acceptable
addition salt with the compounds of the invention there may be mentioned
by way of example, and in a non-limiting manner, sodium, potassium,
calcium and aluminium hydroxides, alkali metal and alkaline earth metal
carbonates, and organic bases, such as triethylamine, benzylamine,
diethanolamine, tert-butylamine, dicyclohexylamine and arginine.
The present invention extends also to a process for the preparation of
compounds of the general formula (I) which is characterised in that a
compound of formula (II):
##STR13##
wherein A is as defined for formula (I) and R' represents a hydroxy,
alkoxy or
##STR14##
radical wherein R" and R"' are other than H and may be alkyls or may form
together with the nitrogen atom carrying them a cyclic amine selected from
pyrrolidine, piperidine and morpholine, is cyclised with phosphorus
oxychloride in the presence or absence of a solvent, such as
N,N-dimethyl-formamide (DMF),
to obtain, after cyclisation, a tricyclic ketone of formula (III):
##STR15##
wherein A is as defined hereinbefore, which is then reacted with
hydroxylamine to obtain an oxime of formula (IV):
##STR16##
wherein A is as defined hereinbefore, which may, if necessary and if
desired, be separated into its E and Z isomers before being reacted with a
compound of formula (V):
##STR17##
wherein R.sub.1, R.sub.2, R.sub.3, x and y are as defined for formula (I)
and X' represents a leaving group which may be a halogen or tosylate, to
yield a compound of formula (I):
##STR18##
wherein A, R.sub.1, R.sub.2, R.sub.3, x and y are as defined hereinbefore,
which may, if necessary and if desired, be separated into its Z and E
isomers and into its possible enantiomers or diastereoisomers, and/or be
converted into a salt with a pharmaceutically-acceptable acid or base.
The present invention relates also to a process for the preparation of
compounds of formula (I) which is characterised in that a compound of
formula (II):
##STR19##
wherein A is as defined for formula (I) and R' represents a hydroxy,
alkoxy or
##STR20##
radical wherein R" et R'" are other than H and may represent alkyls or may
form together with the nitrogen atom carrying them a cyclic amine selected
from pyrrolidine, piperidine and morpholine, is cyclised with phosphorus
oxychloride in the presence or absence of a solvent, such as DMF,
to obtain, after cyclisation, a tricyclic ketone of formula (III):
##STR21##
wherein A is as defined hereinbefore, which is then reacted with an amine
of formula (VI):
##STR22##
wherein R.sub.1, x and y are as defined for formula (I) and X' represents
a leaving group, such as a halogen or tosylate, to obtain a compound of
formula (VII):
##STR23##
wherein A, R.sub.1, X', x and y are as defined hereinbefore, which may:
a) either be reacted with an amine of formula (VIII):
##STR24##
wherein R.sub.2 and R.sub.3 are as defined for formula (I), to yield a
compound of formula (I):
##STR25##
wherein A, R.sub.1, R.sub.2, R.sub.3, x and y are as defined hereinbefore,
which may, if necessary and if desired, be separated into its Z and E
isomers and into its possible enantiomers or diastereoisomers and/or be
converted into a salt with a pharmaceutically-acceptable acid or base,
b) or be reacted with potassium phthalimide to obtain a phthalimide of
formula (IX):
##STR26##
wherein A, R.sub.1, x and y are as defined hereinbefore, which is then
hydrolysed in the presence of hydrazine to yield a compound of formula
(I.sub.A):
##STR27##
wherein A, R.sub.1, x and y are as defined hereinbefore, a particular case
of compounds of formula (I) wherein R.sub.2 =R.sub.3 =H, which may, if
necessary and if desired, be separated into its Z and E isomers and into
its possible enantiomers or diastereoisomers, and/or be converted into a
salt with a pharmaceutically-acceptable acid or base,
which compound of formula (I.sub.A) may, if desired, be alkylated with a
compound of formula (X):
X'--R.sub.5 (X)
wherein X' is as defined hereinbefore and R.sub.5 has the same meaning as
R.sub.2, with the proviso that R.sub.5 cannot represent either hydrogen or
optionally substituted phenyl, to yield a compound of formula (I.sub.B):
##STR28##
wherein A, R.sub.1, R.sub.5, x and y are as defined hereinbefore, a
particular case of compounds of formula (I), which may, if necessary and
if desired, be separated into its Z and E isomers and into its possible
enantiomers or diastereoisomers and/or be converted into a salt with a
pharmaceutically-acceptable acid or base.
The present invention relates also to a process for the preparation of
compounds of formula (I.sub.C):
##STR29##
a particular case of compounds of the general formula (I) wherein A,
R.sub.2 and R.sub.3 are as defined for formula (I) with x=y=1 and R.sub.1
representing a hydroxy group, characterised in that a compound of formula
(II):
##STR30##
wherein A is as defined hereinbefore and R' represents a hydroxy, alkoxy
or
##STR31##
radical wherein R" and R"' are other than H and may be alkyls or may form
together with the nitrogen atom carrying them a cyclic amine selected from
pyrrolidine,, piperidine and morpholine, is cyclised with phosphorus
oxychloride in the presence or absence of a solvent, such as DMF,
to yield, after cyclisation, a tricyclic ketone of the general formula
(III):
##STR32##
wherein A is as defined hereinbefore, which is then reacted with
hydroxylamine to obtain an oxime of the general formula (IV):
##STR33##
wherein A is as defined hereinbefore, which may, if necessary and if
desired, be separated into its E and Z isomers before being reacted, after
metallisation with a metallic hydride, such as sodium hydride, with an
epihalohydrin of the general formula (XI):
##STR34##
wherein Hal represents a halogen atom, to yield, after reaction of the
so-formed intermediate compound with an amine of the general formula
(VIII):
##STR35##
wherin R.sub.2 and R.sub.3 are as defined hereinbefore, a compound of
formula (I.sub.C) as defined hereinbefore, which may, if necessary and if
desired, be separated into its Z and E isomers and into its possible
enantiomers or diastereoisomers, and/or be converted with an acid or a
base into pharmaceutically-acceptable salts.
The compounds of the general formulae (I), (I.sub.A), (I.sub.B), (I.sub.C)
and also the synthesis intermediates used in the above-described processes
may, if necessary, be purified according to one or more methods of
purification selected from crystallisation, chromatography on a silica
column, HPLC on a chiral or non-chiral phase, extraction, filtration and
passage over charcoal and/or resin.
The starting materials used in the above-described processes are either
commercial products or are readily obtainable by the person skilled in the
art in accordance with processes described in the literature or
exemplified in the Preparations described hereinafter.
The compounds of formula (I) possess very valuable pharmacological
properties.
The Applicant has discovered that the compounds of the invention ,very
selectively have a very high affinity for 5HT.sub.3 and/or 5HT.sub.2C
serotoninergic receptors and also for serotonin reuptake sites.
In addition to that very high affinity clearly proved in vitro by receptor
binding studies (determination of the affinity), the activity of the
compounds of the present invention has also been established in vivo in
animal behaviour models (Example B and C of the present Application).
The compounds of the invention may thus be used in the prevention and
treatment of anxiety, depression, stress, psychoses, compulsive
obsessional disorders of schizophrenia, disorders of the central nervous
system, migraine, memory disorders, eating behaviour disorders, disorders
of food intake, alcoholism and pain, and also in the prevention and
treatment of vomiting and disorders of gastric emptying.
The invention extends also to pharmaceutical compositions comprising as
active ingredient at least one of the compounds of formula (I) in pure
form or in the form of a mixture of isomers or one of its
pharmaceutically-acceptable addition salts with an acid or a base, in
combination with one or more pharmaceutically-acceptable excipients or
carriers.
Among the compositions according to the invention there may be mentioned by
way of example, and in a non-limiting manner, those which are suitable for
oral, parenteral, ocular, per- or trans-cutaneous, nasal, rectal,
perlingual or respiratory administration, and especially injectable
preparations, aerosols, eye or nose drops, tablets, sublingual tablets,
soft gelatin capsules, hard gelatin capsules, lozenges, glossettes,
suppositories, creams, ointments and gels.
The preparations so obtained are generally presented in dosage form and may
contain, depending on the disorders treated and the weight, age and sex of
the patient, from 0.01 to 100 mg of active ingredient taken from one to
three times per day, preferably from 0.01 to 5 mg of active ingredient,
especially from 0.1 to 5 mg, for example 1 mg.
The following Examples illustrate the invention but do not limit it in
anyway.
PREPARATION 1
Methyl 3-(pyrrol-1-yl)thiophene-2-carboxylate
At room temperature, add 20 g (0.127 mol) of methyl
3-aminothiophene-2-carboxylate in small portions to a solution of 16.80 g
(0.127 mol) of 2,5-dimethoxytetrahydrofuran in 100 ml of acetic acid.
After 30 minutes' stirring at room temperature, then 90 minutes at
90.degree. C., the acetic acid is removed under reduced pressure and the
residue is taken up in 100 ml of 2N sodium hydroxide solution and
extracted with diethyl ether. After washing with water and rendering
colourless with animal charcoal, the ethereal phase is concentrated to
dryness to yield the title compound.
Yield: 68%
Melting point: 60.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1700 (CO)
PREPARATION 2
3-(Pyrrol-1-yl)thiophene-2-carboxylic acid
A solution of 20 g (0.096 mol) of methyl
3-(pyrrol-1-yl)thiophene-2-carboxylate in a mixture of 150 ml of methanol
and 100 ml of a 6N aqueous sodium hydroxide solution is heated at reflux,
with stirring, for 3 hours. The methanol is removed under reduced pressure
and the reaction mixture is diluted with 100 ml of acidified water and
extracted with 500 ml of ether. The ethereal phase is decanted off, dried
and then concentrated in vacuo, and the title compound is recrystallised
from diethyl ether.
Yield: 74%
Melting point: 170.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1675 (CO), 2980 and 2520 (OH)
PREPARATION 3
Methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
43.8 g (0.292 mol) of 4-chloropyridine hydrochloride and 38.59 g (0.292
mol) of 2,5-dimethoxytetrahydrofuran are stirred for 10 minutes at room
temperature in 600 ml of dioxane. 50 g (0.292 mol) of methyl
4-methyl-3-aminothiophene-2-carboxylate are added and the suspension is
heated at reflux for 3 hours. The dioxane is removed under reduced
pressure, and the residue is taken up in 1 liter of water and then
extracted with 1 liter of diethyl ether. The ethereal phase is washed with
water, decanted off, dried over magnesium sulfate, rendered colourless
with animal charcoal and concentrated under reduced pressure to yield the
title compound.
Yield: 91%
Melting point: 76.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1715 (CO)
PREPARATIONS 4 TO 8
By proceeding in the same manner as for Preparations 1 and 3, but using
suitably substituted methyl thiophenecarboxylates, the compounds
corresponding to Preparations 4 to 8 are obtained.
__________________________________________________________________________
##STR36##
Recrystallisation
Preparation
R.sub.6 R.sub.5 .nu. cm.sup.-1 (KBr)
Melting point
Yield
solvent
__________________________________________________________________________
##STR37## H 1710 (CO)
104.degree. C.
76% diethyl ether
5
##STR38## H 1700 (CO)
91.degree. C.
82% diehyl ether
6 H
##STR39##
1720 (CO)
178.degree. C.
85% ethanol
7 H
##STR40##
1720 (CO)
140.degree. C.
70% ethanol
8 H
##STR41##
1710 (CO)
173.degree. C.
92% acetonitrile
__________________________________________________________________________
PREPARATION 9
Ethyl 4,5-dimethyl-2-(pyrrol-1-yl)thiophene-3-carboxylate
By proceeding as for Preparation 1, the title compound is obtained in the
form of an oil.
Yield: 91%
Infrared: .nu. cm.sup.-1 (KBr): 1720 (C.dbd.O)
##STR42##
.sup.1 H NMR: .delta. (ppm) (DMSO d.sub.6): 1.47 triplet (3H, CH.sub.2
CH.sub.3 ); 2.57 singlet (3H, CH.sub.3(4)); 2.67 singlet (3H,
CH.sub.3(5)); 4.47 quadruplet (2H, CH.sub.2); 6.50 doublet of doublet (2H,
H.sub.3', H.sub.4'); 7.20 doublet of doublet (2H, H.sub.2', H.sub.5').
PREPARATION 10
4,5-Dimethyl-2-(pyrrol-1-yl)thiophene-3-carboxylic acid
The title compound is obtained by proceeding as for Preparation 2.
Yield: 84%
Melting point: 156.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 2530 (OH), 1670 (C.dbd.O)
##STR43##
.sup.1 H NMR: .delta. (ppm) (DMSO d.sub.6): 2.28 singlet (3H, CH.sub.3(4));
2.50 singlet (3H, CH.sub.3(5)); 6.13 doublet of doublet (2H, H.sub.3',
H.sub.5'); 6.84 doublet of doublet (2H, H.sub.2', H.sub.5').
PREPARATION 11
N-[3-(Pyrrol-1-yl)thiophen-2-ylcarbonyl]pyrrolidine
Heat a suspension of 10 g (0.048 mol) of methyl
3-(pyrrol-1-yl)thiophene-2-carboxylate in 40 ml of pyrrolidine at reflux
for 7 hours. The solution is poured into 800 ml of cold water, with
stirring, and the precipitate formed is suction-filtered, washed with cold
water, and then recrystallised from diethyl ether.
Yield: 88%
Melting point: 110.degree. C. (diethyl ether)
Infrared: .nu. cm.sup.-1 (KBr): 1600 (C.dbd.O)
PREPARATION 12
N-[3-(Pyrrol-1-yl)thiophen-2-ylcarbonyl]morpholine
By proceeding in the same manner as for Preparation 11, but using
morpholine instead of pyrrolidine, the title compound is obtained in the
form of white crystals.
Yield: 84%
Melting point: 100.degree. C. (diethyl ether)
Infrared: .nu. cm.sup.-1 (KBr): 1615 (C.dbd.O)
PREPARATION 13
N-[3-(Pyrrol-1-yl)thiophen-2-ylcarbonyl]piperidine
By proceeding in the same manner as for Preparation 11, but using
piperidine instead of pyrrolidine, the title compound is obtained in the
form of yellow crystals.
Yield: 80%
Melting point: 126.degree. C. (diethyl ether)
Infrared: .nu. cm.sup.-1 (KBr): 1625 (C.dbd.O)
PREPARATION 14
N-[3-(Pyrrol-1-yl)-4-methylthiophen-2-ylcarbonyl]pyrrolidine
By proceeding in the same manner as for Preparation 11, but using methyl
4-methyl-3-(pyrrol-1-YL)THIOPHENE-2-carboxylate, the title compound is
obtained in the form of white crystals.
Yield: 83%
Melting point: 178.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1610 (C.dbd.O)
PREPARATIONS 15 TO 19
By proceeding in the same manner as for Preparation 11, but replacing the
methyl 3-(pyrrol-1-yl)thiophene-2-carboxylate with the esters
corresponding to Preparations 4 to 8, the compounds corresponding to
Preparations 15 to 19 are obtained.
__________________________________________________________________________
##STR44##
Recrystallisation
Preparation
R.sub.6 R.sub.5 .nu. cm.sup.-1 (KBr)
Melting point
Yield
solvent
__________________________________________________________________________
15
##STR45## H 1625 (CO)
139.degree. C.
80% diethyl ether
16
##STR46## H 1620 (CO)
154.degree. C.
60% acetonitrile
17 H
##STR47##
1620 (CO)
200.degree. C.
60% acetonitrile
18 H
##STR48##
1620 (CO)
144.degree. C.
70% ethanol
19 H
##STR49##
1610 (CO)
209.degree. C.
58% acetonitrile
__________________________________________________________________________
PREPARATION 20
N-[4,5-Dimethyl-2-(pyrrol-1-yl)thiophen-3-ylcarbonyl]pyrrolidine
Step A: 4,5-Dimethyl-2-(pyrrol-1-yl)thiophene-3-carbonyl chloride
4.45 g (20.1 mmol) of 4,5-dimethyl-2-(pyrrol-1-yl)thiophene-3-carboxylic
acid (Preparation 10) are dissolved in 150 ml of benzene at 10.degree. C.,
then 5.85 g (28.1 mmol) of phosphorus pentachloride are gently added.
After 1 hours' stirring at 10.degree. C., then 2 hours at room
temperature, the reaction mixture is filtered and the benzene is removed
under reduced pressure. The residue is taken up in 500 ml of n-hexane and
then filtered, and the n-hexane is removed under reduced pressure. The
acid chloride obtained is used directly in Step B.
Step B: N-[4,5-Dimethyl-2-(pyrrol-1-yl)thiophen-3-ylcarbonyl]pyrrolidine
The acid chloride obtained in Step A is dissolved in 25 ml of benzene at
0.degree. C. and then 2.92 ml of triethylamine and 13.5 ml of pyrrolidine
are added dropwise in succession. The reaction mixture is stirred for one
hour and then diluted with 50 ml of water, acidified with. 10N
hydrochloric acid and extracted with 300 ml of diethyl ether. The ethereal
phase is washed with water, dried over magnesium sulfate, rendered
colourless with animal charcoal and concentrated under reduced presure to
yield the title compound.
Yield: 74%
Melting point: 100.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1615 (C.dbd.O)
##STR50##
.sup.1 H NMR: .delta. (ppm) (DMSO d.sub.6): 1.70 multiplet (4H, H.sub.3",
H.sub.4"); 2.00 singlet (3H, CH.sub.3(4)); 2.33 singlet (3H, CH.sub.3(5));
3.33 multiplet (4H, H.sub.2", H.sub.3"); 6.20 triplet (2H, H.sub.3',
H.sub.4'); 6.87 triplet (2H, H.sub.2', H.sub.5').
PREPARATION 21
N-[2-(Pyrrol-1-yl)thiophen-3-ylcarbonyl]pyrrolidine
Add 50 ml of pyrrolidine dropwise, at room temperature, to a solution of
2-(pyrrol-1-yl)thiophen-3-ylcarbonyl azide (Heterocycles, (1983), 20, 477)
in 500 ml of dichloromethane. The reaction mixture is stirred for 12 hours
at room temperature and then washed three times with 150 ml of 1N
hydrochloric acid each time and then with 150 ml of water. The organic
phase is then dried over calcium chloride and subsequently concentrated to
dryness to yield the title compound in the form of an oil.
Yield: 73%
Infrared: .nu. cm.sup.-1 (KBr): 1610 (C.dbd.O)
.sup.1 H NMR: .delta. (ppm) (DMSO d.sub.6): 1.66 multiplet (4H); 2.80
multiplet (2H); 3.30 multiplet (2H); 6.20 multiplet (2H, H.sub.3',
H.sub.4'); 6.90 multiplet (2H, H.sub.2', H.sub.5'); 7.03 doublet (1H,
H.sub.4); 7.31 doublet (1H, H.sub.5)
PREPARATION 22
5-Chloro-2-(pyrrol-1-yl)benzoic acid
18.6 ml (0.143 mol) of 2,5-dimethoxytetrahydrofuran are stirred for 10
minutes with 21.5 g (0.143 mol) of 4-chloropyridine hydrochloride in 600
ml of 1,4-dioxane. 24.6 g (0.143 mol) of 2-amino-4-chlorobenzoic acid are
added, and the mixture is heated at reflux for 4 hours. After removal of
the dioxane under reduced pressure, the residue is taken up with 1 liter
of water and extracted with 800 ml of diethyl ether. The ethereal phase is
washed with water and then extracted with 500 ml of a saturated aqueous
sodium hydrogen carbonate solution. The aqueous phase is acidified with
10N hydrochloric acid and then extracted with 800 ml of diethyl ether. The
ethereal phase is washed with water, decanted off, dried over magnesium
sulfate, rendered colourless with animal charcoal and concentrated under
reduced pressure to yield the title compound in the form of a grey powder.
Yield: 95%
Melting point: 178.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 3000 (COOH), 1680 (C.dbd.O)
PREPARATION 23
N-[5-Chloro-2-(pyrrol-1-yl)benzoyl]pyrrolidine
Step A: 5-Chloro-2-(pyrrol-1-yl)benzoyl chloride
10 g (45.1 mmol) of 5-chloro-2-pyrrol-1-ylbenzoic acid are dissolved in 300
ml of benzene at 10.degree. C. and then 13.15 g (63.1 mmol; 1.4 eq.) of
phosphorus pentachloride are gently added. After 1 hours' stirring at
10.degree. C., then 2 hours at room temperature, the reaction mixture is
filtered and the benzene is removed under reduced pressure. The residue is
taken up in 500 ml of n-hexane and then filtered and the n-hexane is
removed under reduced pressure. The acid chloride is obtained in the form
of a red oil which is used directly in Step B.
Infrared: .nu. cm.sup.-1 : 3100 (CH), 1755 (C.dbd.O)
Step B: N-[5-Chloro-2-(pyrrol-1-yl)benzoyl]pyrrolidine
The acid chloride obtained in Step A is dissolved in 50 ml of benzene at
0.degree. C., and 6.5 ml of triethylamine followed by 30 ml of pyrrolidine
are added dropwise. The reaction mixture is stirred for 1 hour and then
diluted with 100 ml of water, acidifed to pH=4 with 10N hydrochloric acid,
and extracted with 300 ml of diethyl ether. The ethereal phase is washed
with water, dried over magnesium sulfate, rendered colourless with animal
charcoal and concentrated under reduced pressure to yield the title
compound in the form of an oil.
Yield: 79%
Infrared: .nu. cm.sup.-1 (KBr): 3100 (.dbd.C--H), 1620 (C.dbd.O)
PREPARATION 24
5-Methyl-2-(pyrrol-1-yl)benzoic acid
The title compound is obtained by proceeding in the same manner as for
Preparation 22, but using the appropriate reactants.
Yield: 77%
Melting point: 124.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 3430 (OH), 1675 (C.dbd.O)
PREPARATION 25
N-[5-Methyl-2-(pyrrol-1-yl)benzoyl]pyrrolidine
The title compound is obtained by proceeding in the same manner as for
Preparation 23, Steps A and B, but using 5-methyl-2-(pyrrol-1-yl)benzoic
acid as starting material.
Yield: 42% in two stages
Melting point: 69.degree. C.
Infrared: .nu. cm.sup.-1 : 2930-2880 (.dbd.C--H), 1630(C.dbd.O)
PREPARATION 26
2-(Pyrrol-1-yl)benzoic acid
Method A
The title compound is obtained by proceeding in the same manner as for
Preparations 22 and 24, but using the appropriate reactants.
Yield: 91.8%
Melting point: 98.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 3460 (OH), 1680 (C.dbd.O)
Method B
Step A: Methyl 2-(pyrrol-1-yl)benzoate
17.14 mol of 2,5-dimethoxytetrahydrofuran and 19.84 g of 4-chloropyridine
hydrochloride in 600 ml of 1,4-dioxane are stirred for 10 minutes at
25.degree. C., and then 17.12 mol of methyl anthranilate are added and the
suspension is heated at reflux for 3 hours. After removal of the dioxane
under reduced pressure, the residue is taken up in 1 liter of water and
extracted with diethyl ether. The ethereal phase is washed with water,
decanted off, dried over magnesium sulfate, rendered colourless with
animal charcoal, and then concentrated under reduced pressure to yield the
title product in the form of an oil.
Yield: 92.7%
Infrared: .nu. cm.sup.-1 (KBr): 2940 (.dbd.C--H), 1710(CO.sub.2 CH.sub.3)
Step B: 2-(Pyrrol-1-yl)benzoic acid
24 g of the ester obtained in the preceding Step are dissolved in a mixture
of 75 ml of methanol and 75 ml of an aqueous 30% sodium hydroxide
solution. After 5 hours' heating at reflux, the methanol is removed under
reduced pressure, the residue is taken up in wetter and acidified with 10N
hydrochloric acid, and the precipitate is isolated by filtration. The
precipitate is taken up in diethyl ether and then the ethereal phase is
washed with water, dried over magnesium sulfate, rendered colourless with
animal charcoal and then concentrated under reduced pressure to give the
title compound in a yield of 65%.
Total yield: 60%
PREPARATION 27
4-Chloro-2-(pyrrol-1-yl)benzoic acid
The title compound is obtained by proceeding in the same manner as for
Preparations 22 and 24, but using the appropriate reactants.
Yield: 88.2%
Melting point: 139.degree. C.
Infrared: .nu. cm.sup.-1 (KBr) 1670 (C.dbd.O)
PREPARATION 28
8H-Thieno[2,3-d]pyrrolo[1,2-a]pyrrol-8-one
##STR51##
A suspension of 0.04 mol of
N-[3-(pyrrol-1-yl)thiophen-2-ylcarbonyl]pyrrolidine (Preparation 11) in 90
ml of phosphorus oxychloride is heated at reflux for 1 hour. After
cooling, the imminium salt formed is isolated by filtration, washed with
petroleum ether and then diethyl ether, dried, and then dissolved in
water. The aqueous phase is rendered alkaline by the dropwise addition of
2N sodium hydroxide solution and then, after 1 hours' stirring, the
precipitate formed is isolated by filtration, washed with water, dried and
then recrystallised from diethyl ether.
Yield: 77%
Melting point: 112.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1670 (C.dbd.O)
This compound can also be obtained by using
N-[3-(pyrrol-1-yl)thiophen-2-ylcarbonyl]morpholine (Preparation 12) and
N-[3-(pyrrol-1-yl)thiophen-2-ylcarbonyl]piperidine (Preparation 13) as
starting materials.
PREPARATIONS 29 TO 34
The compounds corresponding to Preparations 29 to 34 are obtained by
proceeding in the same manner as for Preparation 28, but replacing the
N-[3-(pyrrol-1-yl)thiophen-2-ylcarbonyl]pyrrolidine with the appropriate
amide.
__________________________________________________________________________
##STR52##
Recrystallisation
Preparation
R.sub.6 R.sub.5 .nu. cm.sup.-1 (KBr)
Melting point
Yield
solvent
__________________________________________________________________________
29 H CH.sub.3 1660 (CO)
134.degree. C.
72% diethyl ether
30
##STR53## H 1650 (CO)
196.degree. C.
60% acetonitrile
31
##STR54## H 1660 (CO)
132.degree. C.
70% diethyl ether
32 H
##STR55##
1675 (CO)
186.degree. C.
78% acetonitrile
33 H
##STR56##
1670 (CO)
148.degree. C.
60% ethanol
34 H
##STR57##
1670 (CO)
164.degree. C.
62% ethanol
__________________________________________________________________________
PREPARATION 35
8-Hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole
Heat at reflux for 90 minutes a solution of 0.011 mol of
8H-thieno[2,3-d]pyrrolo[1,2-a]pyrrol-8-one (Preparation 28) and 0.0132 mol
of hydroxylamine hydrochloride in 50 ml of pyridine. After cooling and
after removal of the pyridine under reduced pressure, the residue is taken
up in 150 ml of water and extracted with diethyl ether. The ethereal
solution is dried over magnesium sulfate and then concentrated under
reduced pressure to yield the title compound in the form of a mixture
comprising 70% of the Z form, 30% of the E form.
Yield: 82.8%
Melting point: 172.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 3360 (OH)
PREPARATION 36
3-Methyl-8-hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole
By proceeding as for Preparation 35, the title compound is obtained in the
form of a mixture comprising 70% of the Z form, 30% of the E form.
Yield: 92%
Melting point: 198.degree. C. (70% Z, 30% E mixture)
Infrared: .nu. cm.sup.-1 (KBr): 1635 (C.dbd.N)
The 3-methyl-8-hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole may be
obtained in the form of the pure Z isomer by recrystallisation of the
mixture of Z and E isomers from acetonitrile.
Yield: 33%
Melting point: 204.degree. C. (pure Z isomer)
.sup.1 H NMR: (DMSOd.sub.6): .delta.(ppm): 2.03 singlet (3H,CH.sub.3); 5.86
doublet of doublet (1H,H.sub.6); 6.16 doublet (1H, H.sub.7); 6.96 doublet
(1H, H.sub.5); 7.16 singlet (1H, H.sub.2); 11.49 singlet (1H, .dbd.N--OH)
PREPARATION 37 TO 41
The compounds of Preparations 37 to 41 are obtained by proceeding as for
Preparation 35, but using the compounds of Preparations 30 to 34 as
starting materials.
__________________________________________________________________________
##STR58##
Recrystallisation
Preparation
R.sub.6 R.sub.5 Melting point
Yield
solvent Isomerism
__________________________________________________________________________
37
##STR59## H 210.degree. C.
82% acetonitrile
100% Z
38
##STR60## H 188.degree. C.
76% acetonitrile
80% Z 20% E
39 H
##STR61##
210.degree. C.
80% acetonitrile
70% Z 30% E
40 H
##STR62##
228.degree. C.
72% acetonitrile
100% Z
41 H
##STR63##
226.degree. C.
70% acetonitrile
100% Z
__________________________________________________________________________
PREPARATION 42
7-Chloropyrrolo[1,2-a]indol-9-one
A solution of 8.5 g (30.9 mmol) of
N-[5-chloro-2-(pyrrol-1-yl)benzoyl]pyrrolidine (Preparation 23) in 70 ml
of phosphorus oxychloride is heated at 100.degree. C. for 35 minutes.
After cooling, the precipitate formed is isolated by filtration, washed
with petroleum ether to remove excess phosphorus oxychloride, and then
redissolved in 30 ml of water. The aqueous solution is rendered alkaline
by the dropwise addition of 10% sodium hydroxide solution and the
precipitate formed is filtered and extracted with 100 ml of ethyl acetate.
The organic phase is washed with water, dried over magnesium sulfate,
rendered colourless with animal charcoal and concentrated under reduced
pressure to yield 1.76 g of the title product.
Yield: 27%
Melting point: 92.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 3090 (CH), 1675 (C.dbd.O)
##STR64##
.sup.1 H NMR: .delta.(ppm): (DMSO d.sub.6): 6.33 doublet of doublet (1H,
H.sub.2); 6.80 doublet of doublet (1H, H.sub.1); 7.53-7.47-7.40 multiplet
(4H, H.sub.3, H.sub.5, H.sub.6, H.sub.8)
PREPARATION 43
7-Methylpyrrolo[1,2-a]indol-9-one.
At 0.degree. C., add 1.36 ml (14.9 mmol) of phosphorus oxychloride to 1.14
ml (14.9 mmol) of dimethylformamide, then add a solution of 3 g (14.9
mmol) of 5-methyl-2-pyrrol-1-ylbenzoic acid (Preparation 25) in 30 ml of
dimethylformamide. After one night's stirring at room temperature,
hydrolyse the reaction mixture by pouring into 50 ml of water, extract
with 200 ml of diethyl ether, and wash the ethereal phase in succession
with water, a saturated aqueous hydrogen carbonate solution and then
water. After drying over magnesium sulfate and rendering colourless with
animal charcoal, the ethereal phase is concentrated to dryness to yield
the title compound.
Yield: 35%
Melting point: 85.degree. C.
Infrared: .nu. cm .sup.-1 (KBr): 1670 (C.dbd.O)
PREPARATIONS 44 AND 45
The following are obtained by proceeding in the same manner as for
Preparation 43:
PREPARATION 44
Pyrrolo[1,2-a]indol-9-one
Yield: 50%
Melting point: 126.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1670 (C.dbd.O)
PREPARATION 45
6-Chloropyrrolo[1,2-a]indol-9-one
Yield: 35%
Melting point: 181.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1670 (C.dbd.O)
PREPARATION 46
7-Chloro-9-hydroxyiminopyrrolo[1,2-a]indole
Add 3.9 g (56.1 mmol) of hydroxylamine hydrochloride to a solution of 4.6 g
(22.6 mmol) of 7-chloropyrrolo[1,2-a]indol-9-one in 80 ml of pyridine,
then heat the reaction mixture at reflux for 3 hours. After cooling, the
pyridine is removed under reduced pressure and the residue is taken up in
water and extracted with 300 ml of diethyl ether. The ethereal phase is
washed with 100 ml of 0.5N hydrochloric acid and then with water, dried
over magnesium sulfate, rendered colourless with animal charcoal and then
concentrated under reduced pressure to yield 4.18 g of the title product.
Yield: 84.6%
Melting point: 211.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 3180, 3060, 2880, 1490
##STR65##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 6.40 doublet of doublet (1H,
H.sub.2); 6.70 doublet of doublet (1H, H.sub.1); 7.65-7.55 multiplet (4H,
H.sub.3, C.sub.6 H.sub.3); 12.27 singlet (1H, OH)
PREPARATIONS 47 TO 49
The compounds of Preparations 47, 48 and 49 are obtained by proceeding as
for Preparation 46 but using the compounds of Preparations 43, 44 et 45 as
starting materials.
______________________________________
##STR66##
Prepa- Melting .sup.1 H NMR
ration
R.sub.5
R.sub.6
point Yield .delta. (ppm) (DMSO d6)
______________________________________
47 H CH.sub.3
187.degree. C.
77% 2.35(s, 3H); 6.33(dd, 1H);
6.65(dd, 1H); 7.43-7.25(m,
4H); 11.43(s, OH)
48 H H 186.degree. C.
80% 6.35(dd, 1H); 6.65(dd, 1H);
7.50-7.23-7.13(m, 5H);
11.97(m, 1H)
49 Cl H 195.degree. C.
84% 6.38(dd, 1H); 6.67(dd, 1H);
7.17(dd, 1H); 7.57(m, 2H);
7.77(d, 1H); 12.10(s, 1H)
______________________________________
PREPARATION 50
1,2-Dimethyl-8H-thieno[3,2-d]pyrrolo[1,2-a]pyrrol-8-one
A solution of 7.6 g of
N-[4,5-dimethyl-2-(pyrrol-1-yl)thiophen-3-ylcarbonyl]pyrrolidine
(Preparation 20) in 50 cm.sup.3 of phosphorus oxychloride is heated at 100
.degree. C. for 35 minutes. After cooling, the precipitate formed is
isolated by filtration, washed with petroleum ether to remove excess
phosphorus oxychloride and then redissolved in 25 ml of water. The aqueous
solution is rendered alkaline with 10% sodium hydroxide solution and the
precipitate formed is filtered and extracted with 100 ml of ethyl acetate.
The organic phase is washed with water, dried over magnesium sulfate,
rendered colourless with animal charcoal and concentrated under reduced
pressure to yield 2.8 g of the title product.
Yield: 49.7%
Melting point: 95.degree. C. (decomposition)
Infrared: .nu. cm.sup.-1 (KBr): 1670 (C.dbd.O)
##STR67##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.03 singlet (3H, CH.sub.3(1));
2.20 singlet (3H, CH.sub.3(2)); 6.05 doublet of doublet (1H, H.sub.6);
6.93 doublet of doublet (1 H, H.sub.7); 7.20 doublet of doublet (1H,
H.sub.5)
PREPARATION 51
8H-Thieno[3,2-d]pyrrolo[1,2-a]pyrrol-8-one
The title compound is obtained by proceeding as for Preparation 50, but
using N-[2-(pyrrol-1-yl)thiophen-3-ylcarbonyl]pyrrolidine (Preparation
21).
PREPARATION 52
1,2-Dimethyl-8-hydroxyiminothieno[3,2-]pyrrolo[1,2-a]pyrrole
The title compound is obtained by proceeding as for Preparation 46, but
using 1,2-dimethyl-8H-thieno[3,2-d]pyrrolo[1,2-a]pyrrol-8-one (Preparation
50) as starting material.
Yield: 83%
Melting point: decomposition from 180.degree. C.
##STR68##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.17 singlet (3H, CH.sub.3(1));
2.30 singlet (3H, CH.sub.3(2)); 6.13 doublet of doublet (1H, H.sub.6);
6.53 doublet of doublet (1H, H.sub.7); 7.15 doublet of doublet (1H,
H.sub.5)
PREPARATION 53
8-Hydroxyiminothieno[3,2-d]pyrrolo[1,2-a]pyrrole
The title compound is obtained by proceeding as for Preparation 52, but
using 8H-thieno[2,3-b]pyrrolo[2,1-e]pyrrol-8-one (Preparation 51) as
starting material.
Yield: 90%
Melting point: 250.degree. C. E isomer; 190.degree. C. Z isomer
Infrared: .nu. cm.sup.-1 (KBr): 1635 (C.dbd.N)
##STR69##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): E isomer: 6.15 (1H, H.sub.6);
6.60 (1H, H.sub.7); 7.03 (2H, H.sub.1, H.sub.2); 7.27 (1H, H.sub.5); Z
isomer: 6.12 (1H, H.sub.6); 6.37 (1H, H.sub.7); 7.05 (1H, H.sub.2); 7.21
(1H, H.sub.1) 7.26 (1H, H.sub.5)
EXAMPLE 1
8-[(3-Isopropylamino-2-hydroxy-n-prop-1-yloxy)imino]thieno[2,3-d]pyrrolo-[1
,2-a]pyrrole
##STR70##
Step A:
(Z)-8-[(2,3-Epoxyprop-1-yl)oxyimino]thieno[2,3-d]pyrrolo[2,1-a]pyrrole
Add 0.8 g of sodium hydride to a solution of 4 g (0.021 mole) of
8-hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole in 50 ml of toluene and
10 ml of dimethylformamide. Wait for 15 minutes and then add 2.85 g (0.021
mole) of epibromohydrin. After 7 hours' stirring at room temperature, the
reaction mixture is poured into 200 ml of water, decanted off, dried and
then concentrated to dryness under reduced pressure. The solid obtained is
recrystallised from cyclohexane to yield the Z isomer.
Yield: 35%
Melting point: 100.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 1600 (C.dbd.N)
Step B:
8-[3-1Isopropylamino-2-hydroxyprop-1-yloxy)imino]thieno[2,3-d]pyrrolo[1,2-
a]pyrrole
2 g of 8-[(2,3-epoxyprop-1-yl)oxyimino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole
(Z) are added to 5 ml of an aqueous solution of isopropylamine, then
stirred for 10 hours at room temperature. After hydrolysis and extraction
with diethyl ether, the residual oil obtained is dissolved in 30 ml of
isopropanol at 40.degree. C. After the addition of one equivalent of
oxalic acid, the precipitate formed is suction-filtered, washed with ether
and recrystallised from an isopropanol/propanol (60:40) mixture.
Yield: 65% (oxalate)
Melting point: oxalate 196.degree. C. (50/50 Z/E mixture)
Infrared: .nu. cm.sup.-1 (KBr): (oxalate) 3120-2600 (NH.sub.2+), 1700
(C.dbd.O)
EXAMPLE 2
8-[(3-Cycloheptylamino-2-hydroxyprop-1-yloxy)imino]thieno[2,3-d]pyrrolo-[1,
2-a]pyrrole
The title compound is obtained by proceeding as for Example 1, but
replacing the isopropylamine in Step B with cycloheptylamine.
Yield: 51%
Melting point: base: 118.degree. C.: (50/50 Z/E mixture); oxalate:
186.degree. C.: (50/50 Z/E mixture)
EXAMPLE 3
(Z)-8-{[2-(N,N-Dimethylamino)ethoxy]imino}-3-methylthieno[2,3-d]pyrrolo-[1,
2-a]pyrrole
1.32 g of water and then 3.91 g of 1-chloro-2-(N,N-dimethylamino)ethane
hydrochloride and 5 g of
(Z)-8-hydroxyimino-3-methylthieno[2,3-d]pyrrolo[1,2-a]pyrrole (Preparation
36) are added to 6.99 g of sodium carbonate in 200 ml of anhydrous
acetone. The reaction mixture is heated at reflux for 40 hours, then the
acetone is removed and the residue is taken up in 100 ml of water and then
extracted with 200 ml of diethyl ether. The ethereal phase is washed with
water, decanted off and then dried over magnesium sulfate, and
subsequently concentrated to dryness to yield the title product in the
form of an oil.
Yield: 77%
Preparation of the oxalate salt
4.9 g of the oil obtained above are dissolved in 50 ml of isopropanol at
40.degree. C. and then 1.68 g of oxalic acid are added and the whole is
heated at reflux for 30 minutes. After cooling, the precipitate is
isolated by filtration, washed with diethyl ether and then dried to yield
the title product in the form of the oxalate.
Yield: 68%
Melting point: 200.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 3006, 2700, 2540, 2500, 1725, 1610.
##STR71##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.36 singlet (3H, CH.sub.3);
2.80 singlet (6H, 2.times.CH.sub.3); 3.43 multiplet (2H, CH.sub.2); 4.60
multiplet (2H, CH.sub.2); 6.20 split doublet (1H, H.sub.6); 6.53 split
doublet (1H, H.sub.7); 7.30 split doublet (1H, H.sub.5); 7.56 singlet (1H,
H.sub.2); 10.40 singlet (1H, NHO)
Using 8-hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole in the form of a 70%
Z/30% E mixture as starting material, the title compound is obtained in
the form of a mixture of isomers in proportions equivalent to the starting
proportions.
EXAMPLES 4 TO 38
By proceeding in the same manner as for Example 3, but using the
appropriate aminohaloalkyl and
8-hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole, the compounds of the
following Examples are obtained:
__________________________________________________________________________
##STR72##
Melting
Infrared
Ex.
R.sub.6 R.sub.5 R.sub.3 Salt Yield
Isomer
point .nu. (cm.sup.-1)
__________________________________________________________________________
4 H H
##STR73## oxalate
60% Z/ E 80/20
168.degree. C.
(acetonitrile)
1630 (CN):
2480, 2680
(NH+)
5 H H
##STR74## oxalate
50% Z/ E 90/10
142.degree. C.
(acetonitrile)
1600 (CN);
2500, 2600
(NH+)
6 H H
##STR75## fumarate
20% Z/ E 60/40
130.degree. C.
(isopropanol)
1620 (CN); 2640
NH+)
7 H H
##STR76## fumarate
40% Z/ E 80/20
128.degree. C.
(isopropanol)
1600 (CN); 2620
NH+)
8 H H
##STR77## fumarate
35% Z/ E 90/10
110.degree. C.
(acetonitrile/
1620 (CN); 2600
NH+)
9 H H
##STR78## oxalate
60% Z/ E 90/10
160.degree. C.
(acetonitrile)
1630 (CN); 2600
NH+)
10 H H
##STR79## oxalate
40% Z/ E 90/10
189.degree. C.
(acetonitrile)
1620 (CN); 2660
NH+)
11 H H
##STR80## oxalate
35% Z/ E 80/20
201.degree. C.
(acetonitrile)
1610 (CN); 2680
NH+)
12 H H
##STR81## oxalate
55% Z/ E 60/40
181.degree. C.
(acetonitrile)
1600 (CN); 2600
NH+)
13 H H
##STR82## oxalate
50% Z/ E 70/30
176.degree. C.
(acetonitrile)
1630 (CN); 2680
NH+)
14 H CH.sub.3
##STR83## fumarate
70% Z 188.degree. C.
(acetonitrile)
1600 (CN);
2500, 2660
(NH+)
15 H CH.sub.3
##STR84## fumarate
60% Z/ E 80/20
130.degree. C.
(acetonitrile)
1610 (CN);
2500, 2640
(NH+)
16 H CH.sub.3
##STR85## fumarate
60% Z 200.degree. C.
(acetonitrile)
1600 (CN);
2500, 2640
(NH+)
17 H CH.sub.3
##STR86## oxalate
52% Z 190.degree. C.
(acetonitrile)
1610 (CN);
2500, 2680
(NH+)
18 H CH.sub.3
##STR87## oxalate
50% Z/ E 80/20
149.degree. C.
(acetonitrile)
1620 (CN);
2500, 2660
(NH+)
19 H CH.sub.3
##STR88## fumarate
39% Z 169.degree. C.
(isopropanol)
1600 (CN);
2500, 2600
(NH+)
20 H CH.sub.3
##STR89## fumarate
30% Z 190.degree. C.
(acetonitrile)
1630 (CN);
2500, 2600
(NH+)
21 H CH.sub.3
##STR90## oxalate
12% Z/ E 60/40
123.degree. C.
(isopropanol)
1620 (CN);
2500, 2680
(NH+)
22 H CH.sub.3
##STR91## oxalate
58% Z 166.degree. C.
1610 (CN);
2500, 2900
(NH+)
23 H CH.sub.3
##STR92## oxlaate
65% Z 147.degree. C.
1610 (CN);
2500, 2690
(NH+)
24
##STR93## H
##STR94## oxalate
45% Z/ E 80/20
201.degree. C.
(acetonitrile)
1600 (CN);
2500, 2640
(NH+)
25
##STR95## H
##STR96## oxalate
40% Z/ E 80/20
170.degree. C.
(acetonitrile)
1600 (CN);
2500, 2640
(NH+)
26
##STR97## H
##STR98## oxalate
55% Z/ E 80/20
130.degree. C.
(acetonitrile)
1600 (CN);
2520, 2620
(NH+)
27
##STR99## H
##STR100## oxalate
35% Z/ E 70/30
210.degree. C.
(acetonitrile)
1630 (CN);
2500, 2600
(NH+)
28
##STR101##
H
##STR102## oxalate
50% Z/ E 60/40
191.degree. C.
(acetonitrile)
1600 (CN);
2540, 2600
(NH+)
29
##STR103##
H
##STR104## oxalate
15% Z 90.degree. C.
(acetonitrile/
1600 (CN);
2500, 2600
(NH+)
30
##STR105##
H
##STR106## oxalate
65% Z/ E 60/40
180.degree. C.
(acetontrile)
1600 (CN);
2500, 2640
(NH+)
31
##STR107##
H
##STR108## oxalate
45% Z/ E 60/40
198.degree. C.
(acetonitrile)
1610 (CN);
2540, 2700
(NH+)
32
##STR109##
H
##STR110## oxalate
45% Z/ E 50/50
189.degree. C.
(acetonitrile)
1600 (CN);
2500, 2640
(NH+)
33
##STR111##
H
##STR112## oxalate
55% Z/ E 50/50
199.degree. C.
(acetonitrile)
1615 (CN);
2500, 2620
(NH+)
34
##STR113##
H
##STR114## oxalate
60% Z/ E 60/40
212.degree. C.
(acetonitrile)
1600 (CN);
2540, 2700
(NH+)
35 H
##STR115##
##STR116## oxalate
40% Z/ E 50/50
165.degree. C.
(ethanol)
1630 (CN);
2700, 2640
(NH+)
36 H
##STR117##
##STR118## oxalate
30% Z/ E 50/50
180.degree. C.
(acetonitrile)
1620 (CN);
2700, 2500
(NH+)
37 H
##STR119##
##STR120## oxalate
48% Z/ E 50/50
170.degree. C.
(acetonitrile)
1610 (CN);
2700, 2500
(NH+)
38 H
##STR121##
##STR122## oxalate
50% Z/ E 60/40
280.degree. C.
(acetonitrile/
isopropanol)
1620 (CN);
2700, 2500
__________________________________________________________________________
(NH+)
EXAMPLE 39
3-Methyl-8-{[3-(N,N-dimethylamino)-1-phenylprop-1-yloxy]imino}thieno-[2,3-d
]pyrrolo[1,2-a]pyrrole
Method A
Add 0.75 g (25 mmol) of sodium hydride to a solution of 1 g (4.89 mmol) of
(Z)-3-methyl-8-hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole (Preparation
36) in 50 ml of benzene. After the whole has been heated for 1 hour at
reflux, add 1.15 g (4.89 mmol) of
N,N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride and continue
refluxing for 2 hours. After cooling, the precipitate is filtered off and
the filtrate is concentrated under reduced pressure and then extracted
with diethyl ether. After washing with water and drying, the organic phase
is concentrated to dryness to yield the title compound in the form of a
base which is then converted into a salt in isopropanol with oxalic acid.
Yield: 6%
Melting point: (oxalate): 210.degree. C. (decomposition)
Infrared: .nu. cm.sup.-1 (KBr) (oxalate): 1710 (C.dbd.O)
##STR123##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.33 multiplet (5H, CH.sub.2 and
CH.sub.3); 2.70 singlet (6H, N(CH.sub.3).sub.2); 3.00 triplet (2H,
CH.sub.2 --N); 5.30 multiplet (3H, CH, OH, NH.sup.+); 6.10 doublet of
doublet (1H, H.sub.6); 6.40 doublet of doublet (1H, H.sub.7); 7.30
multiplet (6H, H.sub.9 and C.sub.6 H.sub.5); 7.50 singlet (1H, H.sub.2).
Method B
Heat 1 g of (Z)-3-methyl-8-hydroxyiminothieno[2,3-d]pyrrolo[1,2-a]pyrrole,
1.15 g of N,N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride and 0.8
g of sodium hydroxide in 100 ml of methanol at reflux for 26 hours. After
cooling and removing the methanol under reduced pressure, the residue is
extracted with diethyl ether and then treated as for Method A.
Yield: 15%
EXAMPLE 40
(Z)-3-Methyl-8-[(2-amino-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole
Step A:
(Z)-3-Methyl-8-[(2-bromo-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole
Add 5 g of 2-aminoxy-1-bromoethane hydrobromide, 1.5 mol of glacial acetic
acid and 1.6 ml of pyridine in succession to a suspension of 1.43 g of
3-methyl-8H-thieno[2,3-d]pyrrolo[1,2-a]pyrrol-2-one (Preparation 29) in 70
ml of ethanol. The reaction mixture is heated at reflux for 3 hours, then
the ethanol is removed under reduced pressure and the residue is extracted
with 100 ml of diethyl ether. After washing with water, drying,
concentrating to dryness and working up again in a diethyl ether/petroleum
ether mixture, 1:1, the title compound is obtained in the form of a
powder.
Yield: 23%
Melting point: 92.degree. C.
Infrared: .nu. cm.sup.-1 (KBr): 2950, 2900, 1490
Step B:
(Z)-3-Methyl-8-[(2-phthalimido-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyr
role
Add 0.98 g of potassium phthalimide to a solution of 1.64 g of
(Z)-8-[(2-bromo-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole in 30 ml
of dimethylformamide, then heat the mixture at reflux for 2 hours. After
cooling, the reaction mixture is poured into 200 ml of water and then
extracted with 300 ml of ethyl acetate. The organic phase is washed with
water, dried over magnesium sulfate, rendered colourless with animal
charcoal and then concentrated, and the residue is taken up in a minimum
amount of diethyl ether and then filtered and dried.
Yield: 55%
Melting point: 157.degree. C. (acetonitrile/isopropanol, 8:2)
Infrared: .nu. cm.sup.-1 (KBr): 1710 (C.dbd.O)
Step C:
(Z)-3-Methyl-8-[(2-amino-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole
Add 0.3 ml (6.1 mmol) of hydrazine hydrate to a solution of 0.85 g (2.2
mmol) of
(Z)-3-methyl-8-[(2-phthalimido-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyr
role in 50 ml of a mixture of ethanol/isopropanol, 1:1. The reaction
mixture is heated to reflux. After refluxing the mixture for 30 minutes,
add 0.3 ml of hydrazine hydrate and heat at reflux again for 90 minutes.
Add 0.5 ml of hydrazine hydrate during the course of the 90 minutes'
refluxing. After cooling the reaction mixture, the precipitate formed is
removed by filtration and the filtrate is concentrated under reduced
pressure. The residue is extracted with diethyl ether and the ethereal
phase is washed with water, dried over magnesium sulfate, treated with
animal charcoal and concentrated to yield 200 mg of the title product in
the form of an oil (base).
Preparation of the oxalate salt
Take up the oil obtained above in 40 ml of isopropanol, then add 90 mg of
oxalic acid and heat at reflux for 15 minutes. After cooling, isolate by
means of filtration the precipitate that has formed and wash it with
isopropanol and then with anhydrous diethyl ether.
Yield: 18%
Melting point (oxalate): 200.degree. C.: decomposition (acetonitrile)
Infrared: .nu. cm.sup.-1 (KBr): 1720 cm.sup.-1 (C.dbd.O)
##STR124##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.37 singlet (3H, CH.sub.3);
3.20 triplet (2H, CH.sub.2 --N); 4.37 triplet (2H,O--CH.sub.2); 6.20
multiplet (5H, H.sub.6, NH.sub.3.sup.+ and OH); 6.50 doublet of doublet
(1H, H.sub.7); 7.23 doublet of doublet (1H, H.sub.9); 7.50 singlet (1H,
H.sub.2).
EXAMPLE 41
(Z)-3-Methyl-8-{[2-(N-benzylamino)ethoxy]imino}thieno[2,3-d]pyrrolo[1,2-a]-
pyrrole
Add 1 g (3.2 mmol) of
(Z)-3-methyl-8-[(2-bromo-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole,
0.53 g (3.8 mmol) of potassium carbonate and 0.51 g (4.8 mmol) of
benzylamine in succession to 20 ml of N,N-dimethylformamide. The reaction
mixture is heated at reflux for 3 hours then, after cooling, is poured
into 100 ml of water and extracted with diethyl ether. The ethereal phase
is washed with water, dried over magnesium sulfate, rendered colourless
with animal charcoal and then concentrated under reduced pressure to yield
0.7 g of the title product in the form of an oil (base).
Preparation of the oxalate salt
Take up the oil obtained above in 80 ml of isopropanol, then add 0.2 g of
oxalic acid and heat the reaction mixture at reflux for 30 minutes. After
cooling, isolate by means of filtration the precipitate that has formed
and wash it with isopropanol and then with anhydrous diethyl ether.
Yield: 25%
Melting point (oxalate): 190.degree. C. decomposition (acetonitrile)
Infrared: .nu. cm.sup.-1 (KBr): 1715 (C.dbd.O)
##STR125##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.43 singlet (3H, CH.sub.3);
3.47 triplet (2H, CH.sub.2 --NH); 4.30 singlet (2H, CH.sub.2 --.phi.);
4.60 triplet (2H, OCH.sub.2); 6.27 doublet of doublet (1H, H.sub.6); 6.57
doublet of doublet (1H, H.sub.7); 6.77 multiplet (3H, NH.sub.2.sup.+, OH);
7.30 doublet of doublet (1H, H.sub.5); 7.47 multiplet (6H, H.sub.2,
C.sub.6 H.sub.5).
EXAMPLE 42
(Z)-8-{[2-(N,N-Dimethylamino)ethoxy]imino}thieno[3,2-d]pyrrolo[1,2-a]pyrrol
By proceeding as for Example 3, but replacing the
(Z)-8-hydroxyimino-3-methylthieno[2,3-d]pyrrolo[1,2-a]pyrrole with
8-hydroxyiminothieno[3,2-d]pyrrolo[1,2-a]pyrrole (Preparation 53), the
title compound is obtained in the form of the oxalate in a yield of 70%.
Melting point (oxalate): >260.degree. C. decomposition (acetonitrile)
Infrared: .nu. cm.sup.-1 (KBr) (oxalate): 1725 (C.dbd.O), 1635 (C.dbd.N),
1500, 1090, 960, 900, 835
##STR126##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.75 singlet (6H,
2.times.CH.sub.3); 3.4 multiplet (2H, CH.sub.2); 4.6 multiplet (2H,
CH.sub.2); 6.12 doublet of doublet (1H, H.sub.7); 6.35 doublet of doublet
(1H, H.sub.8); 7.05 doublet (1H, H.sub.2); 7.20 doublet (1H, H.sub.1);
7.25 doublet of doublet (1H, H.sub.6); 10.4 singlet (1H, OH).
EXAMPLE 43
8-{[2-(N,N-Dimethylamino)ethoxy]imino}-1,2-dimethylthieno[3,2-d]pyrrolo-[1,
2-a]pyrrole
By proceeding as for Example 42 but using
1,2-dimethyl-8-hydroxyiminothieno[3,2-d]pyrrolo[1,2-a]pyrrole (Preparation
52) as starting material, the title compound is obtained in the form of
the oxalate in a yield of: 38%
Melting point (oxalate): 176.degree. C. (acetonitrile)
Infrared: .nu. cm.sup.-1 (KBr): 3380, 1710
##STR127##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.13 singlet (3H, CH.sub.3(1));
2.30 singlet (3H, CH.sub.3(2)); 2.77 singlet (6H, N(CH.sub.3).sub.2); 3.40
triplet (2H, CH.sub.2 N); 4.53 triplet (2H, OCH.sub.2); 6.20 doublet of
doublet (1H, H.sub.6); 6.40 multiplet (2H, OH, NH.sup.+); 7.67 doublet of
doublet (1H, H.sub.7); 7.27 doublet of doublet (1H, H.sub.5).
EXAMPLES 44 TO 47
By proceeding as for Example 42, the following are obtaiined:
EXAMPLE 44
8-[(2-Morpholino-ethoxy)imino]thieno[3,2-d]pyrrolo[1,2-a]pyrrole
EXAMPLE 45
8-{[3-N,N-Dimethylamino)-1-phenyl-n-prop-1-yloxy]imino}thieno[3,2-d]pyrrolo
-[1,2-a]pyyrole
EXAMPLE 46
8-[(2-Amino-ethoxy)imino]thieno[3,2-d]pyrrolo[1,2-a]pyrrole
EXAMPLE 47
1,2-Dimethyl 8-[(2-amino-ethoxy)imino]thieno[3,2-d]pyrrolo[1,2-a]pyrrole
EXAMPLE 48
8-[(3-Isopropylamino-2-hydroxy-n-prop-1-yloxy)imino]thieno[3,2-d]pyrrolo
[1,2-a]pyrrole
The title compound is obtained by proceeding as for Example 1.
EXAMPLE 49
7-Chloro-9-{[2-(N,N-dimethylamino)ethoxy]imino}pyrrolo[1,2-a]indole
Add 5 ml of water, 0.94 g (6.5 mmol) of
1-chloro-2-(N,N-dimethylamino)ethane hydrochloride and 1.19 g (5.44 mmol)
of 7-chloro-9-hydroxyiminopyrrolo[1,2-a]indole (Preparation 46) in
succession to a solution of 1.56 g (14.7 mmol) of sodium carbonate in 100
ml of acetone, then heat the reaction mixture at reflux for 36 hours. The
acetone is removed under reduced pressure and the residue is taken up in
50 ml of water and extracted with diethyl ether. The ethereal phase is
washed with water, dried over magnesium sulfate, rendered colourless with
animal charcoal, and then concentrated to dryness to yield the title
product in the form of an oil (base).
Preparation of the oxalate salt
The oil obtained above is taken up in 50 ml of isopropanol and then 1
equivalent of oxalic acid is added and the mixture is heated for 15
minutes at 40.degree. C. After cooling, the precipitate formed is isolated
by filtration and then dried to yield the oxalate salt of the title
compound.
Total yield (oxalate): 23%
Melting point (oxalate): 176.degree. C. (acetonitrile)
Infrared: .nu. cm.sup.-1 (KBr): 3410 (OH); 3030 (CH); 1710 (C.dbd.O)
##STR128##
.sup.1 H NMR: .delta.(ppm) (DMSO d6): 2.80 singlet (6H, 2.times.CH.sub.3);
3.45 multiplet (2H, CH.sub.2 --N); 4.62 multiplet (2H, O--CH.sub.2); 6.38
doublet of doublet (1H, H.sub.2); 6.82 doublet of doublet (1H, H.sub.1);
7.55 multiplet (4H, H.sub.3, C.sub.6 H.sub.3); 10.28 (m, 2H, CO.sub.2 H)
EXAMPLES 50 TO 57
By proceeding in the same manner as for Example 49, but using the
appropriate aminohaloalkyl and 9-hydroxyiminopyrrolo[1,2-a]indole, the
compounds of the following Examples are obtained:
__________________________________________________________________________
##STR129##
Melting NMR
Ex.
R.sub.5
R.sub.6
R.sub.3 Salt Yield
point Infrared
.delta. (ppm) (DMSO
__________________________________________________________________________
d.sub.6)
50 H Cl
##STR130## oxalate, H.sub.2 O
37% 150.degree. C. (sublimation) (acetonitrile
) 3400 (OH); 1610 (CN)
2.80(s, 3H);
3.20-2.30-1.90(m, 9H);
4.47(m, 2H); 6.50(m, 5H);
7.50(m, 3H)
51 H Cl
##STR131## fumarate, H.sub.2 O
17% 138.degree. C. (acetonitrile)
3420 (OH); 1610 (CN)
1.30(m, 3H); 2.50(s, 6H);
2.93- 3.38(m, 2H); 4.43(m,
1H); 6.32 (dd, 1H);
6.50(2H); 6.70(dd, 1H);
7.53(m, 4H)
52 H CH.sub.3
##STR132## oxalate
12% 135.degree. C. (acetonitrile)
3410 (OH); 1600 (CN)
1.35(d, 3H); 2.35(s, 3H);
2.80 (s, 6H); 3.80-3.37(m,
1H); 4.87- 4.53(m, 2H);
6.03(m, 2H); 6.37 (dd,
H.sub.2); 6.77(dd, 1H);
7.53- 7.43-7.30(m, 4H)
53 H CH.sub.3
##STR133## oxalate
40% 190.degree. C. (acetonitrile)
3410 (OH); 1615 (CN)
2.03(m, 6H); 2.35(s, 3H);
2.78 (s, 3H); 3.25(m, 4H);
4.61(m, 1H); 6.21(m, 2H);
6.33(dd, 1H); 6.63(dd, 1H);
7.38-7.23(m, 4H)
54 H H
##STR134## oxalate
27% 183.degree. C. (acetonitrile)
3430 (OH); 1610 (CN)
2.80(s, 6H); 3.43(t, 2H);
4.60(t, 2H); 6.33(dd, 1H);
6.75(dd, 1H); 7.63-7.15(m,
5H)
55 H H
##STR135## oxalate
41% 142.degree. C. (acetonitrile)
3400 (OH); 1610 (CN)
1.37(d, 3H); 2.78(s, 6H);
3.75- 3.55(m, 1H); 4.55(m,
2H); 6.42 (m, 2H);
6.78-6.37(m, 2H); 7.58-
7.15(m, 5H)
56 H H
##STR136## oxalate
28% 157.degree. C. (acetonitrile)
3410 (OH); 1620 (CN)
3.28-1.90(m, 10H); 3.53(t,
2H); 4.17(m, 2H); 6.55(m);
6.33(dd, 1H); 6.73(dd, 1H);
7.53-7.10(m, 5H)
57 Cl
H
##STR137## 0.5 oxalate, H.sub.2 O
46% 160.degree. C. (acetonitrile)
3420 (OH); 1600 (CN)
1.33(d, 3H); 2.77(s, 6H);
3.73- 3.27(m, 1H); 4.53(m,
2H); 6.40 (dd, 1H);
6.78(dd, 1H); 7.23(m, 3H);
7.63-7.53(m, 2H); 7.77(d,
1H)
__________________________________________________________________________
EXAMPLE 58
6-Chloro-9-{[3-(N,N-dimethylamino)-1-phenyl-n-prop-1-yloxy]imino}pyrrolo-[1
,2-a]indole
By proceeding as for Example 39, but replacing the
(Z)-3-methyl-8-hydroxyiminothieno[2,3-d]pyrrolo-[1,2-a]pyrrole with
6-chloro-9-hydroxyiminopyrrolo[1,2-a]indole, the title compound is
obtained, the oxalate salt of which is prepared in a total yield of 23%.
Melting point (oxalate): 120.degree. C. decomposition
Infrared: .nu. cm.sup.-1 (KBr): 1705 (C.dbd.O)
##STR138##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 2.50 triplet (2H, CH.sub.2 --N);
2.73 singlet (6H, N(CH.sub.3).sub.2); 3.13 quadruplet (2H, CH.sub.2); 5.07
multiplet (2H, OH, NH.sup.+); 5.40 multiplet (1H, CH); 6.43 doublet of
doublet (1H, H.sub.2); 7.87 doublet of doublet (1H, H.sub.1); 7.60-7.33
multiplet (8H, C.sub.6 H.sub.3 and C.sub.6 H.sub.5); 7.77 doublet of
doublet (1H, H.sub.3)
EXAMPLE 59
9-[(2-Amino-ethoxy)imino]pyrrolo[1,2-a]indole
Step A: 9-[(2-Bromo-ethoxy)imino]pyrrolo[1,2-a]indole
By proceeding as for Step A of Example 40, but replacing the
3-methyl-8H-thieno[3,2-b]pyrrolo[2,1-e]pyrrol-2-one with
pyrrolo[1,2-a]indol-9-one, 9-[(2-bromo-ethoxy)imino]pyrrolo[1,2-a]indole
is obtained in a yield of 89%.
Melting point: 65.degree. C.
Step B: 9-[(2-Phthalimido-ethoxy)imino]pyrrolo[1,2-a]indole
By proceeding as for Step B of Example 40, but replacing the
(Z)-3-methyl-8-[(2-bromo-ethoxy)imino]-thieno[3,2-b]pyrrolo[2,1-e]pyrrole
with 9-[(2-bromo-ethoxy)imino]pyrrolo[1,2-a]indole,
9-[(2-phthalimido-ethoxy)imino]pyrrolo[1,2-a]indole is obtained in a yield
of 55%.
Melting point: 195.degree. C.
Step C: 9-[(2-Amino-ethoxy)imino]pyrrolo[1,2-a]indole
By proceeding as for Step C of Example 40, but replacing the
(Z)-3-methyl-8-[(2-phthalimido-ethoxy)-imino]thieno[3,2-b]pyrrolo[2,1-e]py
rrole with 9-[(2-phthalimido-ethoxy)imino]pyrrolo[1,2-a]indole, the title
compound, of which the oxalate salt is then prepared, is obtained.
Total yield (oxalate): 48%
Melting point (oxalate): 165.degree. C. decomposition (acetonitrile)
Infrared: .nu. cm.sup.-1 (KBr): 3280, 3090, 2940, 1710, 1620
EXAMPLE 60
9-{[2-(N-Benzylamino)ethoxy]imino}pyrrolo[1,2-a]indole
By proceeding as for Example 41, the title compound is obtained in the form
of a base, and then, after conversion into a salt with oxalic acid, in the
form of the oxalate.
Total yield (oxalate): 16%
Melting point (oxalate): 230.degree. C. decomposition (acetonitrile)
Infrared: .nu. cm.sup.-1 (KBr): 3200, 2830, 1710, 1620, 1480
##STR139##
.sup.1 H NMR: .delta.(ppm) (DMSO d.sub.6): 3.33 multiplet (2H, CH.sub.2
NH); 4.20 singlet (2H, CH.sub.2 -.phi.); 4.57 multiplet (2H, CH.sub.2 O);
6.33 doublet of doublet (1H, H.sub.2); 6.77 doublet of doublet (1H,
H.sub.1); 7.06 multiplet (2H, NH.sup.+, OH); 7.40 multiplet (10H, C.sub.6
H.sub.5, H.sub.3, H.sub.5, H.sub.6, H.sub.7, H.sub.8).
EXAMPLES 61 TO 63
By proceeding as for Example 59, the following are obtained:
EXAMPLE 61
6-Chloro-9-[(2-amino-ethoxy)imino]pyrrolo[1,2-a]indole
EXAMPLE 62
7-Chloro-9-[(2-amino-ethoxy)imino]pyrrolo[1,2-a]indole
EXAMPLE 63
7-Methyl-9-[(2-amino-ethoxy)imino]pyrrolo[1,2-a]indole
EXAMPLES 64 TO 67
By proceeding as for Example 49, the following are obtained:
EXAMPLE 64
9-[(2-Morpholino-ethoxy)imino]pyrrolo[1,2-a]indole
EXAMPLE 65
9-[(2-Piperidino-ethoxy)imino]pyrrolo[1,2-a]indole
EXAMPLE 66
7-Chloro-9-{[2-(N,N-diethylamino)ethoxy]imino}pyrrolo[1,2-a]indole
EXAMPLE 67
7-Methyl-9-{[3-(N,N-dimethylamino)-2-methyl-n-prop-1-yloxy]imino}pyrrolo[1,
2-a]indole
EXAMPLES 68 AND 69
By proceeding as for Example 1, the following are obtained:
EXAMPLE 68
9-[(3-Isopropylamino-2-hydroxy-n-prop-1-yloxy)imino]pyrrolo[1,2-a]indole
EXAMPLE 69
7-Methyl-9-[(3-isopropylamino-2-hydroxy-n-prop-1-yloxy)imino]pyrrolo[1,2-a]
indole
EXAMPLES 70 TO 72
By proceeding as for Examples 41 and 39, the following are obtained:
EXAMPLE 70
8-{[2-(N-Indan-2-ylamino)ethoxy]imino}thieno[2,3-d]pyrrolo[1,2-a]pyrrole
EXAMPLE 71
3-Methyl-8-{[3-(N-indan-2-ylamino)-1-phenylprop-1-yloxy]imino}thieno[2,3-d]
-pyrrolo[1,2-a]pyrrole
EXAMPLE 72
8-{[2-(N-Methyl-N-(3-trifluoromethyl)phenylprop-2-yl)ethoxy]imino}-3-methyl
thieno[2,3-d]pyrrolo[1,2-a]pyrrole
EXAMPLES 73 TO 80
By proceeding as for Example 49, the following are obtained:
EXAMPLE 73
9-{[2-(N-Benzylamino)-n-prop-1-yloxy]imino}pyrrolo[1,2-a]indole
EXAMPLE 74
9-{[2-(N-Benzylamino)-2-isobutyl-ethoxy]imino}pyrrolo[1,2-a]indole
EXAMPLE 75
9-{[2-(N-Benzylamino)-2-phenylethoxy]imino}pyrrolo[1,2-a]indole
EXAMPLE 76
9-{[2-(N-Benzyl-N-methylamino)-2-phenylethoxy]imino}pyrrolo[1,2-a]indole
EXAMPLE 77
9-{[2-(N-Phenylamino)-2-isobutylethoxy]imino}pyrrolo[1,2-a]indole
EXAMPLE 78
9-{[2-(N-Phenethylamino)-n-prop-1-yloxy]imino}pyrrolo[1,2-a]indole
EXAMPLE 79
9-{[2-(N-Methylamino)-2-phenethyl]imino}pyrrolo[1,2-a]indole
EXAMPLE 80
9-{[2-(N-Indan-2-ylamino)ethoxy]imino}pyrrolo[1,2-a]indole
PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION
EXAMPLE A
Study of the Receptor Binding of the Compounds of the Invention
A-1: Study of the binding of the compounds of the invention to 5-HT.sub.3
serotoninergic receptors
The binding of the compounds of the invention to 5-HT.sub.3 receptors was
determined for each compound by measuring the displacement of .sup.3
H-zacopride (specific ligand for 5-HT.sub.3 receptors) in rat area
postrema homogenates.
PROTOCOL
Aliquot amounts (50-100 .mu.l) of a membrane suspension (2.5-5.0 mg of
protein/cm.sup.3) are incubated for 30 minutes at 25.degree. C. in a
Tris-HCl buffer, 25 mM, pH 7,4, in the presence of 0.3-0.4 nM 3.sup.H
-zacopride (83 ci/mmol) (total volume: 0.5 cm.sup.3). The incubation is
terminated by filtering the samples through Whatman GF/B filters which are
then washed and dried. The radioactivity retained on the filters is
finally calculated by spectrometry in liquid medium (Aquasol). The
non-specific binding is evaluated under the same conditions using samples
containing in addition 1 .mu.M of ondansetron (5-HT.sub.3 antagonist). The
displacement curves obtained by adding increasing concentrations of a test
compound to the incubation medium are analysed to determine the affinity
of the test compounds for 5-HT.sub.3 receptors.
A-2: Study of the binding of the compounds of the invention to the
serotonin reuptake site as well as to 5-HT.sub.1, 5-HT.sub.1A,
5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.2, 5-HT.sub.2C, 5-HT.sub.4
serotoninergic receptors.
The binding of the compounds of the invention is measured in accordance
with conventional methods.
for the serotonin reuptake site, by the displacement of .sup.3 H-paroxetine
in rat brain from which the cerebellum has been removed,
for 5-HT.sub.1 receptors, by the displacement of 5-OH tryptamine in pig
frontal cortex and striatum,
for 5-HT.sub.1A receptors, by the displacement of 8-OH-DPAT in rat
hippocampus homogenates,
for 5-HT.sub.1B receptors, by the displacement of 5-hydroxytryptamine in
rat cortex, striatum, and globus pallidus homogenates,
for 5-HT.sub.1D receptors, by the displacement of 5-OH-tryptamine in rat
cortex, striatum and globus pallidus homogenates,
for 5-HT.sub.2 receptors, by the displacement of aminoiodoketaneserine in
rat frontal cortex homogenates,
for 5-HT.sub.2C receptors, by the displacement of N-methylmesulergine in
rat frontal cortex and hippocampus homogenates,
for 5-HT.sub.4 receptors, by the displacement of GR 113808 in guinea pig
striatum or hippocampus.
CONCLUSION
The compounds of the invention appear to possess a very strong affinity for
5-HT.sub.3 and/or 5HT.sub.2C serotoninergic receptors as well as for
serotonin reuptake sites. That strong affinity is doubled by a high
selectivity in relation to other serotoninergic receptors. The IC.sub.50
values obtained for the compounds of the invention are compiled in the
following Table (I):
TABLE (I)
__________________________________________________________________________
IC.sub.50 values obtained for serotonin reuptake sites and serotoninergic
receptors
IC.sub.50 (M)
Serotonin
Ex.
reuptake sites
5-HT.sub.1
5-HT.sub.1A
5-HT.sub.1B
5-HT.sub.1D
5-HT.sub.2
5-HT.sub.2C
5-HT.sub.3
__________________________________________________________________________
3 1.2 .times. 10.sup.-7
2.2 .times. 10.sup.-6
5.8 .times. 10.sup.-6
2.7 .times. 10.sup.-6
4.8 .times. 10.sup.-7
3.1 .times. 10.sup.-6
2.1 .times. 10.sup.-6
1.1 .times. 10.sup.-10
4 8.9 .times. 10.sup.-7
5.5 .times. 10.sup.-7
4.8 .times. 10.sup.-7
6.1 .times. 10.sup.-7
4.1 .times. 10.sup.-7
5.0 .times. 10.sup.-6
8.2 .times. 10.sup.-7
3.5 .times. 10.sup.-9
13 6.0 .times. 10.sup.-7
1.6 .times. 10.sup.-5
>10.sup.-4
3.1 .times. 10.sup.-5
1.1 .times. 10.sup.-5
1.4 .times. 10.sup.-5
1.0 .times. 10.sup.-6
2.0 .times. 10.sup.-9
14 1.1 .times. 10.sup.-6
1.1 .times. 10.sup.-5
2.2 .times. 10.sup.-5
3.2 .times. 10.sup.-5
7.0 .times. 10.sup.-6
4.2 .times. 10.sup.-5
1.8 .times. 10.sup.-5
2.5 .times. 10.sup.-9
15 1.3 .times. 10.sup.-7
1.1 .times. 10.sup.-5
2.1 .times. 10.sup.-5
6.4 .times. 10.sup.-6
4.0 .times. 10.sup.-6
1.3 .times. 10.sup.-5
8.4 .times. 10.sup.-7
5.0 .times. 10.sup.-9
17 3.0 .times. 10.sup.-7
3.0 .times. 10.sup.-6
1.6 .times. 10.sup.-6
3.6 .times. 10.sup.-6
3.2 .times. 10.sup.-6
3.7 .times. 10.sup.-6
7.1 .times. 10.sup.-7
2.0 .times. 10.sup.-9
18 2.6 .times. 10.sup.-7
5.1 .times. 10.sup.-6
5.7 .times. 10.sup.-6
1.4 .times. 10.sup.-5
7.5 .times. 10.sup.-6
5.2 .times. 10.sup.-6
1.2 .times. 10.sup.-6
4.0 .times. 10.sup.-9
22 1.1 .times. 10.sup.-7
6.9 .times. 10.sup.-6
9.0 .times. 10.sup.-6
1.1 .times. 10.sup.-5
6.4 .times. 10.sup.-6
1.1 .times. 10.sup.-5
1.6 .times. 10.sup.-6
1.0 .times. 10.sup.-9
23 5.0 .times. 10.sup.-6
9.6 .times. 10.sup.-6
5.2 .times. 10.sup.-5
2.4 .times. 10.sup.-5
1.1 .times. 10.sup.-5
1.4 .times. 10.sup.-5
2.0 .times. 10.sup.-6
5.4 .times. 10.sup.-9
39 7.2 .times. 10.sup.-8
1.0 .times. 10.sup.-5
1.1 .times. 10.sup.-5
>10.sup.-4
6.7 .times. 10.sup.-6
2.2 .times. 10.sup.-6
6.1 .times. 10.sup.-8
2.0 .times. 10.sup.-7
40 5.8 .times. 10.sup.-7
9.0 .times. 10.sup.-7
3.1 .times. 10.sup.-6
9.2 .times. 10.sup.-7
2.7 .times. 10.sup.-6
1.5 .times. 10.sup.-5
1.8 .times. 10.sup.-7
2.4 .times. 10.sup.-8
41 1.1 .times. 10.sup.-7
2.7 .times. 10.sup.-6
9.2 .times. 10.sup.-6
4.4 .times. 10.sup.-6
1.1 .times. 10.sup.-5
4.1 .times. 10.sup.-6
4.13 .times. 10.sup.-7
2.9 .times. 10.sup.-8
49 1.2 .times. 10.sup.-5
2.4 .times. 10.sup.-6
2.1 .times. 10.sup.-5
1.4 .times. 10.sup.-6
3.1 .times. 10.sup.-6
7.6 .times. 10.sup.-6
1.1 .times. 10.sup.-5
8.6 .times. 10.sup.-8
52 1.3 .times. 10.sup.-5
2.0 .times. 10.sup.-6
3.3 .times. 10.sup.-6
3.8 .times. 10.sup.-6
8.1 .times. 10.sup.-7
8.4 .times. 10.sup.-6
2.3 .times. 10.sup.-6
4.4 .times. 10.sup.-8
53 2.4 .times. 10.sup.-5
8.3 .times. 10.sup.-6
1.4 .times. 10.sup.-5
3.5 .times. 10.sup.-5
5.5 .times. 10.sup.-6
2.2 .times. 10.sup.-5
6.0 .times. 10.sup.-6
3.7 .times. 10.sup.-8
54 9.3 .times. 10.sup.-7
1.4 .times. 10.sup.-7
1.1 .times. 10.sup.-6
1.1 .times. 10.sup.-6
6.9 .times. 10.sup.-7
1.4 .times. 10.sup.-5
1.4 .times. 10.sup.-6
5.7 .times. 10.sup.-9
55 3.2 .times. 10.sup.-7
2.8 .times. 10.sup.-6
3.8 .times. 10.sup.-6
4.4 .times. 10.sup.-6
1.4 .times. 10.sup.-6
1.2 .times. 10.sup.-5
4.1 .times. 10.sup.-6
5.3 .times. 10.sup.-9
__________________________________________________________________________
EXAMPLE B
Anxiolytic Activity Study--Illuminated/Darkened Cages Test on the Mouse
The anxiolytic effects of the compounds of the invention were studied in
accordance with the illuminated/darkened cages test on the mouse (Crawley
et al. (1981), Pharmacol. Biochem. Behav., 15, pp 695-699).
PROTOCOL
The test uses two cages of equal size (20.times.20.times.14 cm) made of
PVC. One is strongly illuminated by a 100 W bulb ("cold" light) and the
other is darkened. The two cages are separated from one another by a small
opaque tunnel (5.times.7 cm). The mice are introduced individually into
the tunnel and, once they have entered the darkened cage for the first
time, a recording is made over a period of 5 minutes, by means of pads
connected to a computer, of the time spent by the animals in the
illuminated cage as well as the number of transfers between the darkened
cage and the illuminated cage. Each experimental group comprises a minimum
of 15 animals.
RESULTS
By comparison with the control, the compounds of the invention,
administered by the intraperitoneal route, cause an increase in the time
spent by the mouse in the illuminated cage as well as an increase in the
number of transfers between the darkened cage and the illuminated cage.
That significant increase of the two parameters studied demonstrates the
prominent anxiolytic activity of the compounds of the invention.
TABLE II
______________________________________
Study of the anxiolytic activity
(Illuminated/darkened cages test)
(Results given as a percentage compared with the control
group)
Example 22 Dose: 15 mg/kg, i.p. route
______________________________________
Time spent in the illuminated cage
+92%*
Number of transfers
+76%*
______________________________________
*p < 0.5
EXAMPLE C
Antidepressant Activity Study--Forced Swimming Test on the Mouse
The antidepressant effects of the compounds of the invention were studied
in accordance with the forced swimming test on the mouse. (Behavioural
despair in mice: a primary screening test for antidepressants, Porsolt R.
D. et al, Arch. Int. Pharmacodyn., (1977), 229, pp. 327-336).
PROTOCOL
The animals are placed for 6 minutes in a cylinder containing water from
which they cannot escape. The period of immobility of the animals is
measured for the last 4 minutes of the test. The test compounds are
administered in a single dose before the test (imipramine being used as
the reference compound).
RESULTS
The immobility of the mouse in the water reflects a depressive state as a
result of the situation in which it finds itself (aversion situation which
it cannot change). Compared with the controls, the compounds of the
invention reduce very significantly the period of immobility of the
animals which, in this test, is indicative of antidepressant properties.
TABLE III
______________________________________
Study of the antidepressant activity
(Forced swimming test)
(Period of immobility expressed as a percentage by comparison
with the control group)
Dose (mg/kg, i.p. route)
Example 32 64
______________________________________
3 -39%* -86%***
39 -53%** --
______________________________________
*p < 0.5
**p < 0.01
***p < 0.001
EXAMPLE D
Tablets each Comprising 5 mg of
(Z)-3-Methyl-8-{[2-(N,N-Dimethyl-Amino)Ethoxy]Imino}Thieno[3,2-b]Pyrrolo[1
,2-a]Pyrrole Oxalate
Formulation for the preparation of 1000 tablets
______________________________________
(Z)-3-methyl 8-{[2-(N,N-dimethylamino)ethoxy]imino}-
5 g
thieno[2,3-d]pyrrolo[1,2-a]pyrrole oxalate
Corn starch 70 g
Wheat starch 70 g
Lactose 300 g
Magnesium stearate 1 g
Silica 1 g
Hydroxypropyl cellulose 2 g
______________________________________
Top